tbuckley/cabot-search huggingface dataset:
Abstract 1669: <i>In vitro</i> and <i>in vivo</i> synthetic lethality: Potent tumor suppression by a novel FLT3/cKIT/CSF1R/CDK19 inhibitor
Authors: Hui Chen, Marc Paradise, Ryan Shepard, Judith Varner
Journal: Cancer Research (2023)

Abstract Tumor cells are characterized by aberrant signal transduction and cell cycle control pathways that lead to unchecked cell proliferation. Unchecked tumor cell proliferation, as well as macrophage proliferation, contributes to tumor growth and spread. Inhibitors of PI3K or MEK signaling pathways can initially inhibit tumor growth until resistance due to upregulation of the alternative pathway develops. We identified a novel allosteric cKIT/FLT3/CSF1R inhibitor that induces synthetic lethality in AML, lung carcinoma, pancreatic carcinoma and other tumor cells and in proliferating macrophages in vitro and in tumors in vivo by simultaneously inhibiting the MEK-ERK and PI3K-AKT pathways and activating stress activated kinase-mediated cell cycle arrest. A series of related cKIT/FLT3/CSF1R/PDGFR allosteric inhibitors suppressed receptor tyrosine phosphorylation as well as downstream MEK-ERK and PI3K-AKT signaling and mTorc1 and cMyc gene expression pathways that control cell growth. Select cKIT/FLT3/CSF1R/PDGFR inhibitors with a unique positioning of a single side chain also inhibited CDK8/19 and stimulated phosphorylation and activation of JNK and p38. JNK activation promoted sustained ATF-2 and cJun-mediated p53 and Chk1/Chk2 activation, thereby promoting cell cycle arrest in G2/M and ultimately, apoptosis. These inhibitors potently suppressed tumor growth in vivo by halting tumor cell and macrophage proliferation in G2/M. They synergized with anti-PD-1 and anti-CTLA-4 and led to tumor eradication and immunological memory formation. These studies identify novel allosteric inhibitors with potent synthetically lethal anti-tumor activity. Citation Format: Hui Chen, Marc Paradise, Ryan Shepard, Judith Varner. In vitro and in vivo synthetic lethality: Potent tumor suppression by a novel FLT3/cKIT/CSF1R/CDK19 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1669.
Abstract 2676: Gender-associated improvement in gemcitabine’s therapeutic outcome by Palmatine
Authors: Meagan Marie Ybarra, Xiaoyu Yang, Amanda Munoz, Michelle Villarreal, Joel Michalek, Li-Ju Wang, Yidong Chen, Ikeno Yuji, Glenn Halff, Susan Weintraub, Rita Gosh, Addanki P. Kumar
Journal: Cancer Research (2023)

Abstract Despite a plethora of therapeutic strategies, improved survival is only modest for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC). Additionally, between 2000 and 2018, pancreatic cancer incidence significantly increased with the greatest increase among women ages 15-35 years. We identified a protoberberine alkaloid, Palmatine (PMT), that was effective in slowing tumor growth and improving therapeutic outcome of gemcitabine (GEM) in pancreatic tumor bearing mice. Interestingly, the improved therapeutic outcome with the combination was observed in a sex-associated manner in mice. Intriguingly, PMT reduced proliferation of cells isolated from surgically resected tumor samples in 71% of female and 33% of male pancreatic cancer patients. We also observed that the correlation between PMT effects on cancer-related biological functions was associated with downregulation of STAT3 signaling. RNA-seq data from STAT3-KD pancreatic cancer cells revealed enrichment of genes associated with fatty acid metabolism. Of these, mRNA expression of ELOVL2 (Elongation of Very Long Chain Fatty Acids-Like 2) was most significantly increased suggesting a negative regulatory role for STAT3 in ELOVL2 expression. In silico analysis of the pancreatic cancer UalcanPan database shows that ELOVL2 is significantly reduced in human pancreatic tumors relative to normal pancreas and that high expression of ELOVL2 is associated with increased survival. The fatty acid elongase, ELOVL2, is involved in the production of docahexaenoic acid (DHA). Our experimental data show that PMT increased ELOVL2 expression. Taken together, these findings suggest the potential utility of PMT in therapeutic sensitization of GEM through deregulation of STAT3-mediated ELOVL2 signaling. These observations further suggest a sex-associated role for PMT in improving outcomes that may in part involve ELOVL2 function. Supported in part through VA Merit Award BX003876 and Owens Foundation pilot (APK). Citation Format: Meagan Marie Ybarra, Xiaoyu Yang, Amanda Munoz, Michelle Villarreal, Joel Michalek, Li-Ju Wang, Yidong Chen, Ikeno Yuji, Glenn Halff, Susan Weintraub, Rita Gosh, Addanki P. Kumar. Gender-associated improvement in gemcitabine’s therapeutic outcome by Palmatine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2676.
Abstract 1536: Machine learning guided engineering of nivolumab for superior physicochemical properties for subcutaneous injection
Authors: Norio Hamamatsu, Naoyuki Kuwabara, Emi Suzuki, Ryo Yamazaki, Misaki Oikawa, Tomonori Tawara, Tomoyuki Ito, Hikaru Nakazawa, Shiro Kataoka, Mitsuo Umetsu
Journal: Cancer Research (2023)

Abstract Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody that is used as a type of cancer immunotherapeutic agent, called a checkpoint inhibitor. Nivolumab is administered by intravenous infusion. Given the recent studies and potential demand for maintenance immunotherapy, the next generation of Nivolumab for subcutaneous injection would be beneficial for patients’ quality of life. We studied whether we could create a Nivolumab variant that has superior physicochemical properties required for a subcutaneous formulation. A machine-learning guided protein engineering technique was used to improve structural stability at little cost of affinity. As a result, a variant showed an increased melting temperature by 10 ºC with a comparable affinity to Nivolumab. Consistent with the result, the variant is resistant to aggregation under heat stress. Nivolumab is seriously aggregated after treatment at 60 ºC, while the variant does not show any aggregation at all. We also present a result of risk assessment of aggregation at high concentrations. Citation Format: Norio Hamamatsu, Naoyuki Kuwabara, Emi Suzuki, Ryo Yamazaki, Misaki Oikawa, Tomonori Tawara, Tomoyuki Ito, Hikaru Nakazawa, Shiro Kataoka, Mitsuo Umetsu. Machine learning guided engineering of nivolumab for superior physicochemical properties for subcutaneous injection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1536.
Abstract 2288: Longitudinal measurement of HPV copy number in cell-free DNA predicts progression-free survival in HPV-positive oropharyngeal cancer patients
Authors: Martyna Joanna Adamowicz, Lara M. Carey, Christelle Robert, Arantza Esnal-Zufiaurre, Sophie J. Warlow, Robert Wescott, Kate Cuschieri, Brendan Conn, Ashley Hay, Iain J. Nixon, Timothy J. Aitman
Journal: Cancer Research (2023)

Abstract Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in global prevalence and is divided into two types dependent on association with human papillomavirus (HPV), with a more favorable prognosis in HPV+ve tumors. Assay of HPV copy number in plasma cell-free DNA (cfDNA) provides a minimally invasive method for detecting and monitoring tumor-derived HPV, with potential for enhancing clinical care. We have evaluated the utility of cfDNA droplet digital PCR (ddPCR) as a method for characterization and longitudinal monitoring of patients with OPSCC in a prospectively recruited cohort of 163 HPV+ve OPSCC patients. ddPCR assay of cfDNA for five HPV types showed overall 96.4% concordance with both p16 immunohistochemistry (IHC) and broad spectrum PCR analysis of solid tumor tissue. Longitudinal sampling in 105 HPV+ve patients, with median follow-up of 29 months, strongly predicted patient outcomes. Progression-free survival, stratified respectively by the presence or absence of detectable HPV cfDNA at a median of 13 weeks post-treatment, was 50% and 88% (p=0.001, hazard ratio 10.0 (95% CI 2.1-47.1)). In three patients sequential HPV measurement indicated cancer recurrence before the presence of clinical symptoms or detection on imaging. In two patients, greater reliance on sequential HPV measurement would have avoided surgical intervention which ultimately did not confirm disease presence. The high concordance of pre-treatment plasma cfDNA-HPV analysis with p16 IHC and HPV-PCR of solid tissue, together with the predictive value and utility of sequentially measured post-treatment cfDNA-HPV copy number, provide a compelling case for the routine use of cfDNA-HPV ddPCR in diagnostic classification and longitudinal monitoring of OPSCC. Citation Format: Martyna Joanna Adamowicz, Lara M. Carey, Christelle Robert, Arantza Esnal-Zufiaurre, Sophie J. Warlow, Robert Wescott, Kate Cuschieri, Brendan Conn, Ashley Hay, Iain J. Nixon, Timothy J. Aitman. Longitudinal measurement of HPV copy number in cell-free DNA predicts progression-free survival in HPV-positive oropharyngeal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2288.
Abstract 339: Exploring the roles of GSDMD in mammary tumorigenesis
Authors: Derek Yisen Zhang
Journal: Cancer Research (2023)

Abstract Breast cancer (BC) is the most frequently diagnosed cancer worldwide, with an ever-increasing incidence rate. While screening and treatment methods have improved markedly over the last three decades, BC remains the leading cause of malignant death in women annually. Therefore, there is an urgent need to identify new biomarkers and therapeutic targets for BC. Recently, dysregulated gasdermin D (GSDMD), a central player of inflammation-induced cell death called pyroptosis, has been shown to be implicated in cancer. However, it is unclear whether GSDMD plays important roles in BC. In addition, the molecular mechanism underlying GSDMD-involved tumorigenesis remains unknown. Here, we discovered that GSDMD is significantly upregulated in BC. We have shown that overexpression or knockout of GSDMD increases or decreases BC cell proliferation, respectively. In addition, we have identified and validated several novel GSDMD-interacting proteins that play important roles in breast cancer. These present findings will not only shed light on the roles of GSDMD in BC tumorigenesis but also provide new preclinical data for future successful treatments of BC patients. Citation Format: Derek Yisen Zhang. Exploring the roles of GSDMD in mammary tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 339.
Abstract 4844: Development of an oxygen consumption rate assay for a standard plate reader
Authors: Ian Marozas, Zhiyang Zeng, Mike Valley, Jolanta Vidugiriene, James Cali, Wenhui Zhou
Journal: Cancer Research (2023)

Abstract Cells generate ATP by two metabolic pathways, oxidative phosphorylation (OXPHOS) and glycolysis. Together, the amount of ATP generated by both OXPHOS and glycolysis define a cell’s metabolic phenotype and fitness. Researchers are interested in methods to characterize cellular metabolic fitness, which can be a powerful a selection criterion for cell-based therapies such as CAR-T cell therapy. Researchers are also interested in measuring the effects of drug treatment on metabolic fitness, to identify metabolic targets for cancer therapeutics and to determine mitochondrial toxicity of novel therapeutics. Here, we have developed a low-cost strategy for a standard plate reader to monitor the rate change of oxygen concentration, or the oxygen consumption rate (OCR), which is a measure of OXPHOS activity. In our assay, oxygen quenches a phosphorescent porphyrin dye in a concentration dependent manner, allowing one to calculate the oxygen concentration of the culture system with the Stern-Volmer relationship. The porphyrin dye is embedded within nanobeads that are suspended above the cell monolayer and the phosphorescence of the beads is measured from the bottom of the well with a standard plate reader. We found that the OCR increased with cell seeding density in three separate cell lines: HEP-G2, HCT-116, and K-562 suspension cells. We showed that inhibitors of the electron transport chain (ETC) decreased OCR, whereas an uncoupler of the electron transport chain, FCCP, increased OCR in a dose dependent manner. Lastly, mitochondrial fitness (e.g., spare respiratory capacity) was determined by sequentially dosing the mitochondria with poisons specific to the different ETC complexes. Citation Format: Ian Marozas, Zhiyang Zeng, Mike Valley, Jolanta Vidugiriene, James Cali, Wenhui Zhou. Development of an oxygen consumption rate assay for a standard plate reader. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4844.
Abstract 2291: Dynamics of genomic instability of circulating tumor DNA in pancreatic cancer patients
Authors: SooBeen Heo, Jung Won Chun, Eun-Hae Cho, Tae-Rim Lee, Chang-Seok Ki, Yun-Hee Kim, Sang Myung Woo, Sun-Young Kong
Journal: Cancer Research (2023)

Abstract Background: Genomic instability of circulating tumor DNA (ctDNA) has been evaluated as a prognostic biomarker in pancreatic ductal adenocarcinoma (PDAC). However, we did not investigated the association of dynamics between baseline and follow-up genomic instability level and patients outcome. Methods: CtDNA I-score which low-depth whole-genome wide copy number alterations calculated by Z-score comparing the relative frequency for each bin with healthy control were investigated in total 87 PDAC patients (N=32 in resectable stage and N=55 in metastatic stage). Follow-up period for resectable and metastatic patients was different after one month, and 2 and 4 months, respectively. Then the association between I-score dynamics at follow-up and survivals (progression free survival (PFS) and overall survival (OS)) were analyzed. Results: The mean I-score represented as 7.212 (6.887 ± 0.073 in 32 resectable patients and 7.536 ± 0.123 in 55 metastatic patients, p &amp;lt; 0.01) at baseline. In recetable patients, I-score decreased upto 6.710±0.03 (p=0.03) after 1 month and dynamics (decrease or increase) of I-score did not showed significant association with PFS and OS with hazard ratio (HR) of 3.6 (range 0.16-79.2 95% Cl) and 3.9 (range 0.3-50.7), respectively. I-score of metastatic patients at 2 and 4 moths were decresed to 7.180±0.062 (p= 0.01) and 7.029±0.056 (p &amp;lt; 0.01). The change of I-score represented association with PFS and OS as HR 2.8 (range 0.9-8.5) and 0.5 (range 0.11-2.20) at 2 months and 1.1 (range 0.2-5.5) and 3.3 (range 0.07-142.7) at 4 months, respectively. Conclusion: Overall I-score decreased after treatment in both resectable and metastatic patients. To investigate impact for outcome of dynamics of genomic instability in ctDNA, we will continue to analyze follow-up data for long term results. Citation Format: SooBeen Heo, Jung Won Chun, Eun-Hae Cho, Tae-Rim Lee, Chang-Seok Ki, Yun-Hee Kim, Sang Myung Woo, Sun-Young Kong. Dynamics of genomic instability of circulating tumor DNA in pancreatic cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2291.
Abstract 1326: Perineural invasion and bone metastases in prostate cancer - is there a link
Authors: Dawid Sigorski, Susana Galli, Sung Hyeok Hong, Ewa Iżycka-Świeszewska, Joanna B. Kitlinska
Journal: Cancer Research (2023)

Abstract Bone metastases are the most common secondary lesions in prostate cancer (PCa) patients. Typically, initial bone metastases develop in the lower part of the spine and pelvis. While this metastatic pattern is not consistent with the random nature of the arterial osseous dissemination, previous reports suggested the role of the retrograde venous spread in this phenomenon. However, clinical data also indicate a positive association between the degree of perineural invasion (PNI) and bone metastases in PCa patients. Yet, the mechanism linking these two means of dissemination remains unknown. To identify the processes involved in the initial PCa dissemination we used the PC3-ML cell line, which was previously shown to trigger bone metastases, in the orthotopic xenograft model. To this end, the cells were injected into the prostates of male SCID/Bg mice and tumor development and progression was followed by magnetic resonance imaging (MRI) and histopathology. MRI indicated local invasion of the primary tumor, which later resulted in the formation of multiple secondary lesions along the lower spine. However, histopathological analysis revealed that these lesions were initiated in the soft tissues surrounding the vertebral column, while the subsequent invasion of the vertebra was the secondary event. The staining for neuronal markers, neurofilament (NF), tyrosine hydroxylase (TH) and neuropeptide Y (NPY), revealed that PCa cells created multicellular clusters spreading longitudinally along the small nerve fibers, particularly in the paraspinal muscle compartment. The staining for the endothelial cell marker, CD31, detected small vessels present within PCa clusters. However, no evident encapsulation of the PCa cells within blood vessels consistent with the retrograde venous spread was observed. Altogether, these results suggest PNI as the main route of the initial local dissemination of the PCa cells toward the bone, which then triggers bone invasion and subsequent hematogenous spread to distant bones. Further mechanistic studies are required to confirm this hypothesis. Citation Format: Dawid Sigorski, Susana Galli, Sung Hyeok Hong, Ewa Iżycka-Świeszewska, Joanna B. Kitlinska. Perineural invasion and bone metastases in prostate cancer - is there a link [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1326.
Abstract 2112: Reporting recommendations for translational cancer genomic studies
Authors: Raffaella Casolino, Philip A. Beer, Nicola Normanno, Zbyslaw Sondka, Andrew V. Biankin
Journal: Cancer Research (2023)

Abstract Background. Inaccuracy and widespread deficiencies in the reporting of translational cancer genomic studies is common and represents a major issue of cancer research. It challenges not only the study interpretation but also the ability to accurately compare studies. The REMARK (REporting recommendations for tumour MARKer prognostic studies) guideline was previously developed to improve the reporting of tumour biomarker prognostic studies. However, it presents several limitations as many aspects of omic-based research are missing. We developed a new guideline to ensure transparency and standardized reporting of clinical cancer genomic studies. Methods. The concept for this checklist was generated after extensive review of current literature which identified major gaps in study reporting, including: insufficient information about study design, population included, and treatments; inappropriate analysis methods; and widespread deficiencies in the reporting of results. Key elements to be addressed in the new checklist were identified by experts in methodology, biostatistics, and preclinical, translational, and clinical cancer genomics (proposing panel). Several reporting guidelines produced for other types of medical research studies were also reviewed. Results. A preliminary draft of the proposed checklist was discussed during the 18th workshop of the International Cancer Genome Consortium (ICGC) in Verona, Italy (13-14 June 2022). Building on that work, the checklist was then re-discussed and improved by the proposing panel. This will serve as a starting point for further discussion among the ICGC, REMARK, the Catalogue Of Somatic Mutations In Cancer (COSMIC), the International Quality Network for Pathology (IQN Path) and other organizations to collect any criticisms, make further revisions, and reach final consensus. Conclusions. The proposed guideline provides a comprehensive overview to educate on good reporting of translational cancer genomic studies. It represents a valuable reference to consider when designing, conducting, and reporting this kinds of studies. After ICGC, REMARK, COSMIC, and IQN Path discussion, revision, and approval, the proposed checklist will be the new standard to be adopted by researchers, editors and reviewers. It will significantly impact future cancer research and patient care. Citation Format: Raffaella Casolino, Philip A. Beer, Nicola Normanno, Zbyslaw Sondka, Andrew V. Biankin. Reporting recommendations for translational cancer genomic studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2112.